Carcinogenesis is a multistage process involving activation of protooncogenes, e.g., ras, and inactivation of tumor suppressor genes, e.g., p53. Analysis of mutations can provide clues to the etiology of these diverse tumors and to the functions of specific regions of the tumor suppressor gene. p53 is a prototype tumor suppressor gene that is well suited for analysis of mutational spectrum in human cancers: a) most common genetic lesion in human cancers; b) reasonable size as a molecular target; and c) may indicate selection of mutations with pathobiological significance. Transitions predominate in colon, brain and lymphoid malignancies. The effects of p53 mutants on wild-type (WT) p53-mediated transcriptional transactivation are cell type-dependent. Mutational hotspots at CpG dinucleotides in codons 175, 245, 248, 273 and 282 may reflect endogenous mutagenic mechanisms, e.g., deamination of 5-methylcytosine to thymidine. Oxyradicals including nitric oxide may enhance the rate of deamination. p53 may protect the genome from endogenous DNA damage by modulating expression of nitric oxide synthase-2 in a negative feedback loop. Deletions and insertions are most likely the result of DNA polymerase slippage and strand misalignment. p53 may be a sensor of DNA damage and can initiate the assembly of the nucleotide excision repair complex via its binding to XPB and XPD in the transcription-repair factor, TFIIH. p53 can also initiate an apoptosis pathway by its binding to XPB and XPD, which is independent of p53 transcriptional transactivator activity. These results disclose a novel nontranscriptional pathway of p53-induced apoptosis.